Blood vessels in humans and animals are grouped as arterial and venous, determined by whether the blood in it is flowing away from (arterial) or toward (venous) the heart. Veins collect blood from organs, muscle, connective tissue and skin. Venous blood has a low content of oxygen and nutrients, but enriched in carbon dioxide and final metabolism products.
Caused by acquired functional weakness due to lack of activity or by congenital defects, a large number of people show venous congestion in the legs. Congestion means a presence of blood above the physiological level. If no change in habits occurs, congestion turns into insufficiency within few years. Insufficiency means that vein valves become incompetent, resulting in a reversed blood flow. In a vicious circle insufficiency further increases venous blood congestion, and the disease increases with time. Varicose veins develop from insufficiency, they are superficial veins which have been stressed by an overload of blood for years and therefore show large diameters and a tortuous course. Incompetent leg veins are found in 21-25% of people aged 35 or above, and spider veins even in 50% (Uldis Maurins, Barbara H. Hoffmann, Christian Lösch, Karl-Heinz Jöckel, Eberhard Rabe, Felicitas Pannier: Distribution and prevalence of reflux in the superficial and deep venous system in the general population—results from the Bonn Vein Study, Germany. Journal of Vascular Surgery, Vol 48, Issue 3, September 2008, 680-687).
Beside the cosmetic issues, insufficient and varicose veins lead to major complications, due to the congestion and the poor circulation through the affected limb. The complications comprise pain, heaviness, inability to walk or stand for long hours, skin inflammation, skin damage predisposing skin loss or skin ulcers especially near the ankle, usually referred to as venous ulcers, severe bleeding from minor trauma, blood clotting within affected veins (thrombophlebitis, thrombosis, embolic events). Some vascular malformations like Klippel-Trénaunay-Weber of syndrome also go along with varicose veins.
For dilated veins, surgical removal of the target structure, e.g. varicose veins, has been a widely used therapy for decades. However, like all surgical treatments this may be accompanied by several, partially serious adverse effects, i.e. damaging of adjacent arteries, nerves or lymphatic vessels, generation of wounds and cicatrices, wound infections, or intolerance of the patient for narcotic drugs. Furthermore, the tissue damage going along with every surgery, in particular in junction regions like the groin or the popliteal area seems to induce the growth of new, but diseased veins.
As an alternative to surgical removal, different ways of endovenous closure methods have been developed, allowing minimal-invasive treatments with a very low complication rate.
The term endovenous means, therapy is performed by catheter access through the venous system, and within the diseased vein. Catheters are small-lumen tubes, inserted via a single puncture site. The aim of these methods is the permanent closure of the treated vein or vein segment. The effect may be obtained by thermal treatment (e.g. by laser, radiofrequency, steam), or by injection of chemical agents (fluids, foams, adhesives). Due to the use of catheters and probes, thermal treatment and gluing is restricted to relatively linear vessels while chemical agents may also reach curved and tortuous segments and branched or reticular veins.
The effect of all the named endovascular methods applied to peripheral veins is to permanently denature functional proteins in the innermost tissue layer, the so-called endothelial cell layer. Said denaturing process triggers the aggregation of blood cells, in particular thrombocytes, at the vein wall. It is a kind of artificial thrombosis which occludes the vein. In contrary to incidental thrombosis which may be hoped to resolve, in the therapeutic approach the aim is to completely denaturize all the endothelium in the segment to treat. Only parts of the vessel wall sufficiently reached by the thermal or sclerotic effect can be expected to close permanently, while undamaged endothelium will revitalize and lead to recurrent pathologic blood flow. All endovenous procedures are associated with a local vein spasm, due to effects passing the endothelium layer and reaching the muscular layer. Spasm means a contraction of muscular cells, leading to an immediate reduction of the vein diameter. The vein spasm trigger by endovenous techniques is in general not lasting longer than minutes above the activity of the trigger. However, it would be desirable to maintain the spasm or the by spasm reduced vein size as long as it takes the blood within the treated vein to clot, organize and fix the vein size. Occlusion and decrease in vessel diameter are the two most important aims of this kind of therapy. A real initial shrinking could only be obtained by an effect reaching deep into the muscular layer with a permanent shortening of fibers. On the other hand, with increasing effects on the muscular layer the danger of vein perforation increases, and so does pain during and after treatment as there are only micrometers distance to the highly innervated outer wall layer called adventitia. All so far existing sclerosants or thermo-occlusive techniques do not solve these problems and therefore are of limited value. The use of adhesives could be a future solution, but techniques are still insufficient and effective biocompatible and totally biodegradable are not yet available for intravascular use.
Simple sclerotherapy is known for more than 60 years. Today's common liquid sclerosant drugs are e.g. alcohols with detergent properties like polidocanol or sodium tetradecyl sulphate. In the eldest modality, the liquid sclerosant drug is injected via metallic cannulas directly into the vessels. Due to its high flowability the liquid sclerosant drug flows with the blood stream and quickly mixes with blood, soon reaching ineffective dilutions. Blood protein bindings additionally limit the effect of fluid sclerosant agents.
In order to circumvent some drawbacks of the liquid sclerosant drugs, it has been established to produce a sclerosant foam by mixing the liquid sclerosant drug with a gas. The resulting sclerosant drug foam is injected into the target structure, e.g. the varicose vein. For foaming the sclerosant drug (e.g. sodium tetradecyl sulfate or polidocanol) is mixed with sterile air or a physiological gas (carbon dioxide, oxygen) in a syringe or by using mechanical pumps.
In the literature, the terms “foam sclerotherapy”, “sclerofoam”, “microfoam” and “sclerosant drug foam” are used. Sclerofoam can be produced by mixing liquid sclerosant with a medical gas like O2 or CO2, or room air, using the TESSARI method by 10-20 times to- and from injection from one syringe to another via stopcock or Luer-connector, by shaking a syringe, simultaneous aspiration of fluid and gas, or mechanically by pumps, positive or negative pressure devices, perforated outlets or valves, or by propellers or rotating brushes (GEROULAKOS G.: Foam sclerotherapy for the management of varicose veins: a critical reappraisal, Phlebolymphology Vol 13, No. 4 (2006) p 181-220).
If injected properly, foam will replace blood totally for a certain time, varying from seconds to a few minutes. In this time, the contact to the vein wall is more intense than in case of a liquid bolus just passing by. The chemical reaction of the sclerosant on the endothelium (innermost wall layer) will expand to the media layer and trigger muscular spasms, which may be more intense than in the case of fluid sclerosants of the same chemical concentration.
Foaming increases the surface area of the drug. Due its higher stiffness and viscosity, the sclerosant drug foam is more efficacious in causing sclerosis than the liquid sclerosant drug (Thickening of the vessel wall and sealing off the blood flow; Yamaki T, Nozaki M, Iwasaka S: Comparative study of duplex-guided foam sclerotherapy and duplex-guided liquid sclerotherapy for the treatment of superficial venous insufficiency, 2004, Dermatol Surg 30 (5): 718-22; Evaluation of the Efficacy of Polidocanol in the Form of Foam Compared With Liquid Form in Sclerotherapy of the Greater Saphenous Vein: Initial Results; Claudine Hamel-Desnos, Philippe Desnos, Jan-Christoph Wollmann, Pierre Ouvry, Serge Mako, François-Andre Allaer, Dermatol Surg 29 (12): 1170-1175 (2003); WO 95/00120 J. Cabrera et al. 1995).
Besides the viscosity, an important property of sclerofoam is its visibility in ultrasound scans due to the contents of gas which reflects the sound energy (FIG. 1). Therefore, foam injections can be ultrasound monitored and the dosage can be adapted to the individual requirements, which is not feasible with fluid sclerosants as their signal does not differ from fluid blood.
However, the gas may accumulate and lead to acoustic shadows, hiding relevant anatomic structures. It is rarely possible to tell if all the lumen is completely filled with foam, or if there is just a layer of foam floating on blood (FIG. 1).
Although some ultrasound contrast media have been developed, e.g. US 20020031476 A1 disclosing a stabilized gas emulsion containing phospholipids for ultrasound contrast enhancement, or U.S. Pat. No. 4,466,442 A disclosing carrier liquid solutions for the production of gas microbubbles as contrast medium for ultrasonic diagnostics using tensides, such media have not been used to optimize sclerotherapy.
In clinical practice the majority of sclerotherapies are not complete in the sense of total circumferential endothelium denaturation. For example, in case of slow injection, and as well in case of complex and tortuous varicose formations which limit the injection velocity, foam will float on blood instead of replacing it. Only partial denaturation of the endothelium will be achieved. Trials have shown that even by axially turning the patient for 180 degrees the foam will not sufficiently reach the opposite vein walls.
There are some more drawbacks of common sclerofoam: If an injection is performed too fast, foam will also spread to healthy veins and may lead to unintended closures or thrombosis. When a vein shrinks after foam injection by foam-induced spasm to a percentage of its original diameter, significant amounts of foam will migrate to diseased or healthy neighbouring vessels with the same consequence. Common foams are mechanically too weak to resist and stay in place.
In the initial experience it was most welcome that the foam collapses within a short time, coming from the idea of rapid elimination. However, due to rapid foam collapse all the chemicals are transferred to the circulation within minutes which may lead to side effects like bronchospasms or vision disorders. The lack of stability seems to be the most important drawback of common sclerosant foams.
The process of sclerotherapy in detail is this: If sclerofoam is injected into a diseased vein, it replaces the blood, touches the vein wall and triggers a vein spasm. This can be felt during foam injection as an increase of resistance, which is regarded as a sign to stop the injection. As native side branches now have low flow resistance compared to the spastic target vein, a further injection would go there which is normally not intended. If a foam injection is stopped in time, undisturbed collateral flow will dilute small amounts of overdosage and prevent side effects.
The musculature of spastic veins will relax within 5-60 minutes after foam injection, and remainders of common foam will at the latest then be washed off. When the vein spasm vanishes, blood will return to the target vessel. Although by external compression (stockings, bandages) the amount of blood returning to the treated vein can be reduced to some extent, it cannot be avoided effectively or even completely.
The vein will close within several hours to few days after foam injection. However, vein closure may not only occur due to endothelium denaturation, but also if just parts of the endothelium have been denaturized, as occlusive thrombus may form there and reduce or stop the blood flow. Then further parts of vein segment will close due to thrombosis, which will appear as a success. However, all thrombotic occlusion in regions without complete endothelium denaturation is reversible as endothelium is still vital. Therefore, any closure proved by ultrasound examination within days or weeks post treatment does in no way prove endothelium destruction or a success of foam treatment. If closure of this kind occurs, it will not be complete, not stable, or show early relapse. In fact, many cases of “relapse” within the first years represent failed primary endothelium destruction, caused by insufficient foam distribution.
In the case of incomplete endothelium destruction, thrombotic and recanalisation phases will compete and clinically appear as painful phlebitis. This is often clinically more intense than general inflammatory reactions after endothelium denaturation.
An optimized foam should be able to completely replace blood in a diseased vein due to much higher viscosity, and thus solve the problem of incomplete foam treatments.
At the point of primary vein closure, there is no more perfusion in this vessel, and the pathological backward flow is eliminated. This is the same hemodynamic effect like achieved by surgery (“elimination of reflux”), and it is the main endpoint of treatment quality.
In contrary to surgery, the vein is still in place. For optimal results, it should now be neither visible nor palpable. The patient should not feel its existence when moving or at rest. However, this aim is not reached for larger veins by today's sclerotherapies. The reason is that these techniques only trigger a complex process of shrinking and organization which will take weeks to many months, depending on the size of the vein.
Frequently, the vein regains the same diameter it had before treatment. The total amount of clotted blood contained in the vein at the time of total occlusion will determine the duration and symptoms of the organization process. Clotted blood within the vessel will have to be removed by metabolism, performing a change from a large thrombotic vein to a small string of connective tissue. As a fact, the incidence of unwanted side effects like painful inflammations, brownish discolorations, long-lasting indurations and still visible varicose veins rises with the vein diameter and may occur in up to 80% of the treated cases.
It is assumed that the effect of sclerofoam treatments depends on its physical stability. The stability of foam sclerosants is appreciated by the so called volume half life, telling the time until 50% of the foam is collapsed. Common volume half lives of polidocanol microfoams made in silicone-free plastic syringes are 60-180 s. Using glass syringes and forced foaming procedures by to- and from injections from one syringe to another, volume half times of 210 s can be obtained and much better results are observed after applying this kind of foam.
So, one major aim for an optimized foam sclerosant is, to obtain a prolonged volume half life. If achievable, also the effect on the endothelium would be stronger. Using the same concentration of sclerosant, the denaturing effect would grow with the time of interaction to the vessel wall. The dosage of the chemical agent could potentially be reduced.
As sclerofoams of prior kind disintegrate quickly, the rate of unwanted side effects is high: Thrombosis (occlusion of deep veins) caused by migrated foam appears in a rate of up to 4%. Unwanted closure of healthy epifascial veins is estimated at up to 20%, while the clinical sequelae are yet unknown.
Most of conventional foam therapies require several sessions for the aimed success. Sometimes, treatment plans consist of 5-10 visits. This is time consuming for patient and physician. Also the wearing time of bandages or stockings is prolonged.
Summarizing, when treating diseased veins with common sclerotherapy techniques, many attempts are incomplete, induce relevant side effects or frequently show relapse. The diseased vein will not be permanently closed at the end of the procedure. There may remain a space consuming and symptomatic structure for weeks to months. It would be advantageous to have means for instantaneous and permanent closure of diseased veins.
There have been several attempts to improve foam sclerotherapy. WO 2006/037735 A1 discloses a device for producing a medical foam by using sealed containers for sterile sclerosant and sterile gas, which contributes to hygienic aspects and simplification of the procedure as gas and sclerosant do not have to be aspirated from larger containers. However the insufficient physical features of the foam remain unchanged.
Improved therapeutic sclerofoams generated by pressurized gas are disclaimed in U.S. Pat. No. 8,091,801 B2. However, also these foams hardly reach volume half times above a few minutes.
The generation of therapeutic microfoam with gases like carbon dioxide or xenon has been proposed to reduce side effects induced by large amounts of slow resorbable gases like nitrogen, e.g. disclaimed in U.S. Pat. No. 7,357,336 B2. However, such side effects are rarely seen when applying foam volumes less than 10 cc per session. The technical foam properties are not significantly changed, in particular the half-live remains insufficiently short.
To overcome all the drawbacks of sclerosant drugs and sclerosant drug foams of prior art the ideal sclerosant substance has to fulfill a variety of features: It should have a significantly increased consistency or stiffness to fill the target vein completely and precisely. The viscosity should be adjustable for different approaches, e.g. less viscous for injection in small and long cavities, or highly viscous for short or large cavities. It should allow injection via catheters. It should induce long lasting spasms of the target structures. After injection into the target structure foam should remain within said structure until its completed occlusion. Foam within the target vein should dissolve slowly to reduce the inflow of chemical agents to the circulation. For this purpose, the foam should have a volume half-life of hours to days. It should be clearly visible in ultrasound scans but, nevertheless, it should not produce relevant acoustic shadows and always show all relevant tissue and vessel structures. It furthermore has to be safe for application in humans, in particular rates for unwanted side effects like thrombosis or embolism should be significantly lower than in former foam techniques and products. It finally should not contain other chemicals than the sclerosant, and should be 100% biocompatible and biodegradable. Thus the problem is to provide a sclerosant drug foam with the desired properties.